Progenitor Cell Marker Aldehyde Dehydrogenase 1a3 Defines a Subset of Failing Pancreatic Beta Cells in Diabetic Mice

Insulin-producing beta cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, sets the stage for progression from beta cell dysfunction to beta cell dedifferentiation. In this study, we sought to isolate and functionally characterize failing beta cells, as a preliminary step to identify pathways to reverse dedifferentiation. Using various experimental models of diabetes, we found a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH+) as beta cells become dedifferentiated. Flow-sorted ALDH+ islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH+ cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV, and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of beta cell failure. RNA-Sequencing analysis of 2 different cell types in 2 different genotype categories.糖尿病进展过程中，产胰岛素的β细胞会发生去分化（dedifferentiation）。选择氧化磷酸化底物的能力受损，即代谢灵活性不足，为β细胞功能障碍向β细胞去分化进展奠定了基础。本研究旨在分离功能衰竭的β细胞并对其进行功能表征，作为识别逆转β细胞去分化通路的前期研究步骤。通过多种糖尿病实验模型，我们发现随着β细胞发生去分化，乙醛脱氢酶1亚型A3（ALDH+）的表达显著富集。经流式分选的ALDH+胰岛细胞表现出葡萄糖诱导的胰岛素分泌受损，Foxo1与MafA表达缺失，并包含Neurogenin3阳性亚群。RNA测序（RNA-Sequencing）分析显示，ALDH+细胞具有以下特征：(i) 氧化磷酸化及线粒体复合物I、IV、V功能受损；(ii) RICTOR通路激活；(iii) 表达祖细胞标志物。我们提出，在β细胞衰竭的自然病程中，线粒体功能受损标志着从代谢灵活性不足到β细胞去分化的进展过程。本研究对2种不同基因型分类下的2种不同细胞类型开展了RNA测序（RNA-Sequencing）分析。